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Giant cell arteritis (GCA) typically presents with headache, scalp tenderness or visual disturbance. Other symptoms include orofacial pain, constitutional symptoms and ischaemic stroke. An 81-year-old woman with a background of type-2 diabetes and hypertension presented with headache, oral pain and right visual loss. Examination showed hypertension, nodular temporal arteries, reduced visual acuity and suspected oral candida. Inflammatory markers were raised and she was diagnosed with GCA and commenced on corticosteroids. During treatment she developed tongue ulceration, then acute vertigo and incoordination with nystagmus and ataxia. Neuroimaging confirmed bilateral, cerebellar ischaemic strokes and temporal artery biopsy was consistent with GCA. With corticosteroids and secondary prevention of stroke measures she is now functionally independent. Oral pain is an uncommon symptom of GCA and delays in recognition may lead to catastrophic consequences. Clinicians should be aware of uncommon presentations and to optimise additional ischaemic stroke risk-factors.

Objective Combination biological therapies are being considered increasingly for patients with multiple co-morbidities requiring biologics. There are limited data available on this approach, and concerns remain about the possible risk of adverse events, particularly infection. Methods We present three patients on dual biologics for rheumatic disease and asthma. The biologic combinations used were etanercept and mepolizumab, infliximab and omalizumab, and etanercept and omalizumab. The time on combination biologic therapies ranged from 24 to 36 months. Patients were monitored for any serious adverse events. Results All three patients were able to tolerate combined biologic therapies, with no serious adverse events. All three patients gained improvement in their rheumatic and asthma disease control, with reduction in disease activity scores and reduction in steroid usage. Conclusion The decision to start dual biologic therapy should be considered carefully, on a case-by-case basis. The number of patients who are on combination biological therapy is small, and data are sparse. Real-world data are needed to examine the long-term benefits and risks of different forms of combination biologic therapies.

Decision-making involves weighing up the outcome likelihood, potential rewards, and effort needed. Previous research has focused on the trade-offs between risk and reward or between effort and reward. Here we bridge this gap and examine how risk in effort levels influences choice. With outcome uncertainty, people’s risk attitudes follow a fourfold pattern, varying with the domain (gains or losses) and probability (rare or common). Three experiments assessed people’s risk attitudes for money, physical effort, and mental effort. With monetary gambles, risk attitudes followed the classic fourfold pattern, and people were risk averse for increases in money (gains). With both physical and mental effort, however, people exhibited a “flipped” fourfold pattern of risk preferences and were instead risk seeking for increases in effort. Overall, these findings indicate that people treat effort as a loss of resources and are more willing to take risks to avoid potentially high levels of effort.

When people make risky decisions based on past experience, they must rely on memory. The nature of the memory representations that support these decisions is not yet well understood. A key question concerns the extent to which people recall specific past episodes or whether they have learned a more abstract rule from their past experience. To address this question, we examined the precision of the memories used in risky decisions-from-experience. In three pre-registered experiments, we presented people with risky options, where the outcomes were drawn from continuous ranges (e.g., 100-190 or 500-590), and then assessed their memories for the outcomes experienced. In two preferential tasks, people were more risk seeking for high-value than low-value options, choosing as though they overweighted the outcomes from more extreme ranges. Moreover, in two preferential tasks and a parallel evaluation task, people were very poor at recalling the exact outcomes encountered, but rather confabulated outcomes that were consistent with the outcomes they had seen and were biased towards the more extreme ranges encountered. This common pattern suggests that the observed decision bias in the preferential task reflects a basic cognitive process to overweight extreme outcomes in memory. These results highlight the importance of the edges of the distribution in providing the encoding context for memory recall. They also suggest that episodic memory influences decision-making through gist memory and not through direct recall of specific instances.

Many models of choice assume that people retrieve memories of past experiences and use them to guide evaluation and choice. In this paper, we examine whether samples of recalled past experiences do indeed underpin our evaluations of options. We showed participants sequences of numerical values and asked them to recall as many of those values as possible and also to state how much they would be willing to pay for another draw from the sequence. Using Bayesian mixed effects modeling, we predicted participants’ evaluation of the sequences from both the average of the values they recalled and the average of the values they saw. Contrary to the predictions of recall-based models, people’s evaluations appear to be sensitive to information beyond what was actually recalled. Moreover, we did not find consistent evidence that memory for specific items influenced evaluation of sequences. We discuss the implications for sampling models of memory and decision-making and alternative explanations.

An unexamined assumption in many studies of learning and decision making is that people learn underlying probability distributions. However, the acquisition of distributional knowledge is rarely the focus of investigations. We report five experiments (N = 580 adults) that provide this focus and highlight the factors that impact people’s ability to accurately learn and reproduce underlying distributions. We find that people accurately reproduced the distribution only when either the environmental signal is strong (i.e., non-noisy discrete bimodal distributions), or sufficient cues are provided to aid construction of mental representations (e.g., items from the modes in a noisy bimodal distribution are presented in different colours). Together the results challenge strong assumptions about the role of probability distribution-knowledge in explanations of learning and decision making.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services, with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Patients with systemic lupus erythematosus (SLE) are at increased risk of viral infections, and recent data suggests they may be at an increased risk of poor outcomes with COVID-19. This may be particularly true for those on rituximab or high dose steroids. A huge international effort from the scientific community has so far resulted in the temporary authorisation of three vaccines which offer protection against SARS-CoV-2, with over 30 other vaccines being evaluated in ongoing trials. Although there has historically been concern that vaccines may trigger disease flares of SLE, there is little convincing evidence to show this. In general lupus patients appear to gain good protection from vaccination, although there may be reduced efficacy in those with high disease activity or those on immunosuppressive therapies, such as rituximab or high dose steroids. Recent concerns have been raised regarding rare clotting events with the AstraZeneca/Oxford vaccine and it is currently unknown whether this risk is higher for those patients with secondary antiphospholipid syndrome. With the possibility of annual COVID vaccination programmes in the future, prospective data collection and registries looking at the effect of vaccination on SLE disease control, the incidence of COVID-19 in SLE patients and severity of COVID-19 disease course would all be useful. As mass vaccination programmes begin to roll out across the world, we assess the evidence of the use of vaccines in SLE patients and in particular vaccines targeting SARS-CoV-2.

Both memory and choice are influenced by context: Memory is enhanced when encoding and retrieval contexts match, and choice is swayed by available options. Here, we assessed how context influences risky choice in an experience-based task in two main experiments (119 and 98 participants retained, respectively) and two additional experiments reported in the Supplemental Material available online (152 and 106 participants retained, respectively). Within a single session, we created two separate contexts by presenting blocks of trials in distinct backgrounds. Risky choices were context dependent; given the same choice, people chose differently depending on other outcomes experienced in that context. Choices reflected an overweighting of the most extreme outcomes within each local context rather than the global context of all outcomes. When tested in the nontrained context, people chose according to the context at encoding and not retrieval. In subsequent memory tests, people displayed biases specific to distinct contexts: Extreme outcomes from each context were more accessible and judged as more frequent. These results pose a challenge for theories of choice that rely on retrieval as guiding choice.

Summary Background Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1–2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6–8 × 107 cells, or 1·8–2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. Findings Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3–4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. Interpretation These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. Funding Servier.

Background/Aims Part 2 of the GIACTA trial explored the maintenance of efficacy in giant cell arteritis (GCA) patients. It showed that nearly half the patients treated with weekly tocilizumab (TCZ) maintained remission, though flares did still occur in the remaining half when TCZ was discontinued. Currently, NHS England has approved the use of TCZ in GCA for only 1 year as this duration was agreed upon by clinical experts to be sufficient to sustain remission. However, this remains a point of concern amongst clinicians as to whether data from real-life patients confirms that 1 year of TCZ can achieve sustainable remission. Methods Our objective is to assess the real-world experience of TCZ withdrawal in GCA patients and how different centres are trying to mitigate risk of relapse after its cessation. We are conducting a patient survey across six hospitals in Wessex, United Kingdom. Our aim is to assess the change in clinical features, acute phase reactants and the rate of sustained remission and relapse. Results 53 patients with GCA were included in the survey. Average age of patients was 73.5 years. 36 patients had cranial GCA, five had large vessel vasculitis and no sub-type was mentioned for the 12 remaining patients. Temporal artery biopsy was the most common diagnostic tool used for 21 patients, followed by PET scan for 14 patients. Eight patients had a clinical diagnosis only, while seven were diagnosed with GCA based on findings of Anterior Ischaemic Optic Neuropathy. Only three patients had their diagnosis confirmed via ultrasound temporal arteries. Out of these 53 patients, 45 started Tocilizumab. 15 patients stopped treatment due to side effects. Of the remaining 30 patients, only 17 have completed their 1 year of TCZ so far. Two patients relapsed 6 months after stopping TCZ. One of them was on methotrexate (MTX) and low dose prednisolone, while other was on mycophenolate mofetil only. Of those who are currently stable since completing TCZ, five patients are on MTX with prednisolone, one patient on leflunomide and prednisolone, four patients on prednisolone only and three patients on MTX only. Two patients are on no treatment currently. Conclusion This is an ongoing study. Our figures so far show that most patients are still on treatment with steroids and MTX, either alone or in combination, after completing 1 year of TCZ. This could be due to clinicians trying to mitigate against relapse once TCZ is withdrawn. This study highlights that real-world data on relapse/remission rates following TCZ withdrawal is essential as it will help shape future GCA treatment and guidelines. Disclosure S. Khalid: None. B. Davidson: None. N. Hopkinson: None. A. Mason: None. M. Malik: None. F. Laskou: None. L. Parker: None.

Background/Aims Antimalarials have an important role in the management of autoimmune rheumatic disease, especially lupus (SLE) and other connective tissue diseases (CTD). A large North American study demonstrated a risk of retinopathy with hydroxychloroquine, increasing at doses above 5mg/kg and after 10 years or more of continuous therapy. This has influenced the development of specific monitoring ocular guidance for hydroxychloroquine although there has been less attention to potential side effects in routine use. Our aim was to examine hydroxychloroquine use including the effect of changes in ophthalmology guidance Methods We designed a 21-question internet-based survey. This requested information on antimalarials including hydroxychloroquine brand, dosing, monitoring and concerns about use. We requested information about alternatives to hydroxychloroquine including mepacrine and chloroquine, barriers to and indications for prescribing these alternative antimalarials. Results We received 69 responses, 59 (86%) Consultants, 10 (14%) ST’s from across the United Kingdom of which 51% worked in a district general hospital (DGH) setting. Of the Consultants, 28 (47%) ran dedicated CTD clinics. Regarding hydroxychloroquine, 39 respondents (57%) used a defined local pathway for Hydroxychloroquine retinopathy screening. While 59/69 (86%) did not know which hydroxychloroquine brand their pharmacy dispensed, of the remainder, 14/19 (74%) used Quinoric. Regarding hydroxychloroquine dosing, 83% targeted weight-based maintenance dosing with most of these (77%) maintaining at the currently recommended 5mg/kg body weight or less, while 23% used 6.5mg/Kg. No participants measured hydroxychloroquine drug levels. Potential ocular toxicity, cardiac arrythmias and skin hyperpigmentation were reported as the most significant concerns with hydroxychloroquine usage. Of the alternatives, mepacrine was never used by 39%, (77% for chloroquine) while only 4% used either often or very often. Barriers to prescription of these alternative antimalarials were most commonly GP or local Pharmacy unavailability (39% and 17 retrospectively). However, mepacrine/ hydroxychloroquine combination was used by 32% of respondents, most often for refractory skin disease (21 respondents), refractory joint disease (five respondents) and as a steroid sparing drug (six respondents). Conclusion Our results suggest several aspects in which hydroxychloroquine use could be improved. Although recent evidence demonstrates the potential for significant ocular toxicity with Hydroxychloroquine in those taking > 5mg/kg body weight and for >10 years we found practice still varied with 43% Rheumatologists not using a dedicated ocular screening pathway making monitoring long term potentially hazardous. Alternatives to hydroxychloroquine are not considered by 39% perhaps reflecting paucity of data for mepacrine and chloroquine, especially in circumstances including pregnancy but also cost and lack of availability. Our results suggest a need for standardised hydroxychloroquine monitoring processes including improved ophthalmic screening with Optical Coherence Tomography, a need for more evidence about the potential benefits and hazards of hydroxychloroquine and alternative antimalarials and availability of prescribing guidelines. Disclosure A. Kaul: Consultancies; Dr Kaul has received fees for Advisory Boards for AbbVie, Janssen, Novartis, Lilly. Member of speakers’ bureau; r Kaul has received speaker fees from AbbVie, Novartis, Janssen, Leo, Pfizer. A. Mason: None. C. Edwards: None. E. Vital: None.

The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0).UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia.Servier.

In many important real-world decision domains, such as finance, the environment, and health, behavior is strongly influenced by experience. Renewed interest in studying this influence led to important advancements in the understanding of these decisions from experience (DfE) in the last 20 years. Building on this literature, in this perspective, we suggest ways the standard experimental design should be extended to better approach important real-world DfE. These extensions include among others the introduction of more complex choice situations, delayed feedback, and social interactions. Acting upon experiences in these richer and more complicated environments requires extensive cognitive processes to make a decision. Therefore, we argue for integrating cognitive processes more explicitly into experimental research in DfE. These cognitive processes include attention to and perception of numeric and non-numeric experiences, the influence of episodic and semantic memory, and the mental models involved in learning processes. Understanding these basic cognitive processes can advance the modeling, understanding and prediction of DfE in the laboratory and in the real world. We highlight the potential of experimental research in DfE for theory integration across the behavioral, decision, and cognitive sciences. Furthermore, this research could become an important method to better inform decision making and policy interventions.

Associative learning is the process whereby humans and other animals learn the predictive relationship between cues in their environment. This process underlies simple forms of learning from rewards, such as classical and operant conditioning. In this chapter, we introduce the basics of associative learning and discuss the role that memory processes play in the establishment and maintenance of this learning. We then discuss the role that associative learning plays in human memory, including through paired associate learning, the enhancement of memory by reward, and the formation of episodic memories. Finally, we illustrate how the memory process influences choice in decision-making, where associative learning allows people to learn the values of different options. We conclude with some suggestions about how models of associative learning, memory, and choice can be integrated into a single theoretical framework.

Case report - Introduction An interesting case of an 11-year recurrent isolated lateral rectus myositis. Initially responsive to short courses of oral steroids; however, this has more recently become refractory and now the patient is unable to wean off steroids. The use of biologics in these patients is uncommon and there are very few case reports of this and the outcomes. We present a case of refractory orbital myositis treated with rituximab. Case report - Case description A 38-year-old female presented in 2009 with ocular pain, swelling and diplopia. After review by the ophthalmology team an MRI orbits was requested which showed swelling and enhancement of the right lateral rectus muscle, consistent with orbital myositis. She had no other symptoms of myositis elsewhere, and no other symptoms suggestive of a connective tissue disease. Her ANA, ENA and extended myositis panel were negative and therefore aetiology was uncertain. She had no past medical history, but was later diagnosed with hypothyroidism with positive TPO antibodies. Throughout the 11 years since diagnosis her thyroid disease has been well controlled, and she has had normal free T3/T4 and TSH. It was felt that thyroid eye disease was unlikely to present with a single muscle. She was initially treated with a course of 40mg oral prednisolone reducing over 6 weeks and symptoms resolved. In 2013 she had her first relapse, which was treated with prednisolone reducing over the course of 12months, and again symptoms resolved. Her third relapse in 2019 was treated with steroids, but patient was unable to wean off this, requiring 60mg of prednisolone, and at this point was referred to rheumatology for steroid sparing agents. Between 2013 and 2019 there was MRI progression with volumetric enlargement of the right lateral rectus with intra-orbital space reduction. Under the care of rheumatology, she had repeat connective tissue disorders and myositis screen. She was started on azathioprine as a steroid sparing agent. This had little effect and she was still debilitated by orbital pain and diplopia, and unable to reduce her prednisolone below 30mg daily. She trialled intra-orbital steroid injections with little benefit. She has now been started on rituximab infusions to allow us to wean steroids. Thus far she has had two doses and we await the outcome from this treatment. Case report - Discussion Orbital myositis can be a debilitating condition causing diplopia and pain, as in the case of this 38-year-old female who has been off work for the past year due to the condition. It can affect single muscles or multiple muscles and may be unilateral or bilateral. The major differential diagnosis is thyroid eye disease which would not usually cause an isolated myopathy, is usually painless and slowly progressive and as such was felt unlikely to be the underlying pathology in this case. From a literature review into idiopathic orbital inflammation, including myositis, 75% of patients are found to have a good response to corticosteroids. Second-line treatments include radiotherapy, methotrexate/azathioprine and other biologic agents. A case report in 2014 of 10 patients with orbital myositis refractory to steroids and at least one other immunosuppressant, demonstrated that rituximab was safe and effective, with 7/10 patients noting improvement of their symptoms. Out of those seven patients, four had been on steroids at induction of rituximab and all of the patients were able to reduce their steroid dose. The patients in this trial received two initial doses of rituximab and were permitted to have a further dose at 24 weeks if there were recurrence of symptoms. Four out of the seven patients required a further infusion after 24 weeks. In a review of the literature, we have noted a further two case reports of the use of rituximab in orbital myositis from 2008 and 2012 with good response. Both patients were unable to wean from corticosteroids and had tried other DMARDs such as methotrexate. Other case reports of biologics therapy include a case report of two patients in which adalimumab was used and allowed steroid reduction with good results for at least 9 months. Case report - Key learning points

When deciding between different courses of action, both the potential outcomes and the costs of making a choice should be considered. To date, most studies of risk-sensitive choice have focused on the probability of different reward amounts. Here we studied choice between options that varied in the riskiness of the effort (number of responses) required. People made repeated choices between pairs of options that required them to click different numbers of sequentially presented response circles. Easy (low effort) options led to small numbers of response circles, whereas hard (high effort) options led to larger numbers of response circles. For both easy and hard options, safe options led to a fixed effort, whereas risky options led to variable effort that, with a 50/50 chance, required more or less effort. Participants who showed a preference for easier over harder options (63% in Experiment 1 and 93% in Experiment 2) were risk averse overall. Participants were more risk averse for decisions involving hard options than for decisions involving easy options. On subsequent memory tests, people most readily recalled the hardest outcome, and they overestimated its frequency of occurrence. Strikingly, memory for the effort associated with each risky option strongly correlated with risky choices for both easy-effort and hard-effort choices, suggesting that the memory may determine choices based on risky effort.

Background/Aims Myopathies due to inborn errors of metabolism can be difficult to differentiate from inflammatory myopathies. Careful history, examination and laboratory tests are required to establish the diagnosis. We present a case of Riboflavin Transport Deficiency (Brown-Vialetto-Van Laere syndrome) masquerading as an inflammatory myopathy. Methods A 37-year-old lady presented with severe proximal muscle weakness. She had background of sensory neuropathy and chronic anaemia. Notably, her sister had a history of similar symptoms. Creatine Kinase (CK) was 360 IU/L and lactate dehydrogenase (LDH) was 1700 IU/L. Inflammatory markers were normal. The Ro52 antibody was weakly positive. Electromyography showed evidence of a sensory neuropathy with myopathic features. There was symmetrical fatty infiltration and atrophy of the thigh muscles on magnetic resonance imaging (MRI). Positron emission tomography (PET-CT) scan showed widespread intense uptake in skeletal muscle groups. She was given 3 pulses of IV methyprednisolone followed by oral prednisolone which did not provide clinical benefit. Intravenous immune globulin was given when she developed bulbar weakness, with difficulty swallowing and breathing. She required non-invasive ventilation and nasogastric feed. There were necrotic and regenerative muscle fibres on the muscle biopsy, in keeping with rhabdomyolysis. Electron microscopy showed abundant lipid accumulation, suggestive of a metabolic disorder. Urinary organic acids were raised, triggering an acylcarnitines blood spot test, which were increased. This was compatible with riboflavin transport 'Brown-Vialetto-Van-Laere syndrome'. Riboflavin 500mg TDS was started resulting in significant clinical improvement. Prednisolone was weaned, genetic testing sent, and she was transferred for neurorehabilitation. Results Riboflavin Transport Deficiency (Brown-Vialetto-Van Laere syndrome) is an autosomal recessive neurodegenerative genetic disorder. It affects females and males equally. Symptoms can appear in infants as well as adults. These include hearing and visual loss, bulbar palsy leading to dysphagia and speech problems. Paralysis of diaphragm may cause breathing difficulty. Initially it affects the proximal muscles and then generalized muscle weakness. Molecular genetic testing is required to confirm diagnosis. Patients may have abnormal plasma levels of flavin or acylcarnitine. Acylcarnitines are biological intermediates, used in the diagnosis of fatty acid oxidation disorders. Treatment includes riboflavin supplementation and supportive measures. Response to treatment is variable. Conclusion This lady was initially managed as inflammatory myopathy but did not respond to high dose methylprednisolone. There were atypical features including normal inflammatory markers, MRI thighs showing predominantly fatty infiltration and muscle atrophy and the muscle biopsy with abundant lipid accumulation suggestive of a metabolic disorder. We are awaiting full results of genetic testing. This case is a reminder of the importance of tissue diagnosis and reassessing the initial diagnosis if the clinical picture changes or patients do not respond as expected to treatment. Disclosure M. Malik: None. A. Mason: None. B. Davidson: None. J. Furby: None.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Historical evidence suggests that Lupus patients have a higher incidence of several viral infections. This is likely due to a combination of immune dysfunction, immunosuppressive therapy and excess co-morbidities. In this context there has been concern that Lupus patients may be at a higher risk of developing COVID-19 and suffering a severe disease course. As a result, many Lupus patients have been advised to ‘shield’ by isolating from social contact in the hope that this will reduce the likelihood of infection. Early clinical data does not appear to show that the incidence of COVID-19 is higher in Lupus patients. Reassuringly, the clinical course of COVID-19 in Lupus does not generally seem to be more severe than in the general population. There has been huge interest in repurposing existing drugs as potential treatments, including several used to treat Lupus. Of these, corticosteroids and hydroxychloroquine are the most well researched so far. The current evidence suggests that the corticosteroid dexamethasone improves outcome for the sickest COVID-19 patients requiring respiratory support. Initial reports suggested that hydroxychloroquine could have a positive impact on the course of COVID-19, however larger prospective studies have not supported this. Janus kinase inhibitors, currently being investigated for efficacy in lupus, have been shown to have anti-viral effects in vitro and inhibiting the JAK-STAT pathway may dampen down the host hyper-inflammatory response. Several trials are ongoing to assess the outcome of the use of JAK inhibitors in COVID-19 positive patients. For most patients continuing with their existing therapies to prevent a lupus flare or adverse events associated with sudden corticosteroid withdrawal is important whilst an Individualised risk assessment remains vital.

BackgroundAn important element of effective clinical practice is the way physicians think when they encounter a clinical situation, with a significant number of trainee physicians challenged by translating their learning into professional practice in the clinical setting. This research explores the perceptions of educators about how trainee physicians develop their clinical thinking in clinical settings. It considers what educators and their colleagues did to help, as well as the nature of the context in which they worked.MethodA qualitative approach was used in this study with in depth interviews carried out with educators as key informants. Rich data derived from 15 interview transcripts were analysed thematically in a rigorous and iterative process.ResultsThree broad and overlapping themes were identified: working in an educationally minded culture; proximity of the educator to the trainee physician; and trajectory of the trainee physician. The departments in which these educators worked emphasised the importance for the education of trainee physicians. All members of the team were responsible for education of the team, and all members, particularly senior nurses, were able to give feedback upon the trainee physicians’ progress. Educators described working side by side with their trainee physician and frequently being in close proximity to them which means that the educator was both easily accessible and spent more time with their trainee physicians. They described a trajectory of the trainee physicians through the placement with close monitoring and informal assessment throughout.ConclusionRecommendations are made as to how trainee physicians can be supported to develop their clinical thinking. Educators and managers can analyse their own and their department’s practice and select the recommendations relevant to their local circumstances in order to make change. This study adds the educator perspective to a body of literature about the importance of context and supportive learning environments. As such the discussion is applicable to the education of other health professionals.

Background An important element of effective clinical practice is the way physicians ‘think’ when they encounter a clinical situation, with a significant number of physicians in training challenged by translating their learning into professional practice in the clinical setting. This research explores the perceptions of educators about how physicians in training develop their clinical thinking in clinical settings. It considers what educators and their colleagues did to help, as well as the nature of the ‘context’ in which they worked. Method A qualitative approach was used in this study with in depth interviews carried out with educators as ‘key informants’. Rich data derived from fifteen interview transcripts were analysed thematically in a rigorous and iterative process. Results Three broad and overlapping themes were identified: working in an educationally minded culture; proximity of the educator to the physician in training; and trajectory of the physician in training. The departments in which these educators worked emphasised the importance on the education of physicians in training. All members of the team were responsible for education of the team, and all members, particularly senior nurses, were able to give feedback upon the physicians’ in training progress. Educators described working side by side with their physician in training and frequently being in close proximity to them, which means that the educator was both easily accessible and spent more time with their physicians in training. They described a trajectory of the physicians in training through the placement with close monitoring and informal assessment throughout. Conclusion Recommendations are made as to how physicians in training can be supported to develop their clinical thinking. Educators and managers can analysis their own and department’s practice and select the recommendations relevant to their local circumstances in order to make change. This study adds the educator perspective to a body of literature about the importance of context and supportive learning environments. As such the discussion is applicable to the education of other health professionals.

Dementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.

Reward is thought to enhance episodic memory formation via dopaminergic consolidation. Bunzeck, Dayan, Dolan, and Duzel [(2010). A common mechanism for adaptive scaling of reward and novelty. Human Brain Mapping, 31, 1380–1394] provided functional magnetic resonance imaging (fMRI) and behavioural evidence that reward and episodic memory systems are sensitive to the contextual value of a reward—whether it is relatively higher or lower—as opposed to absolute value or prediction error. We carried out a direct replication of their behavioural study and did not replicate their finding that memory performance associated with reward follows this pattern of adaptive scaling. An effect of reward outcome was in the opposite direction to that in the original study, with lower reward outcomes leading to better memory than higher outcomes. There was a marginal effect of reward context, suggesting that expected value affected memory performance. We discuss the robustness of the reward memory relationship to variations in reward context, and whether other reward-related factors have a more reliable influence on episodic memory.

Declarative memory has been found to be sensitive to reward-related changes in the environment. The reward signal can be broken down into information regarding the expected value of the reward, reward uncertainty and the prediction error. Research has established that high as opposed to low reward values enhance declarative memory. Research in neuroscience suggests that high uncertainty activates the reward system, which could lead to enhanced learning and memory. Here we present the results of four behavioural experiments that examined the role of reward uncertainty in memory, independently from any other theoretically motivated reward-related effects. Participants completed motivated word learning tasks in which we varied the level of reward uncertainty and magnitude. Rewards were dependent upon memory performance in a delayed recognition test. Overall the results suggest that reward uncertainty does not affect episodic memory. Instead, only reward outcome appears to play a major role in modulating episodic memory.

The “construction” view of preference holds that we sample information from memory in the moment to make judgments and decisions. Building on previous work examining the relationship between memory performance and judgment, we used incentive-compatible methods to investigate both the extent to which memory supports evaluation and the potential trade-off between online and memory-based retrospective evaluation. In a series of pre-registered experiments, we presented people with a sequence of numerical values and asked them to complete either a free recall task, a willingness to-pay (WTP) task, or both. Using Bayesian mixed effects modeling, we predicted WTP (for the values in the remembered sequence) from both recalled items and presented items, and examined how the position of a value in a sequence determined its contribution to overall evaluation. Uniquely, we compared models of overall performance in memory across trials (e.g., primacy and recency) with those that predict evaluation from specific items recalled on individual trials. Previous studies are likely to have underestimated the strength of the relationship by focusing only on general trends in memory performances. Our findings indicated that memory predicts evaluation when examined at the level of individual people and individual sequences. We replicate the findings that when participants anticipate a judgment task, they show less accurate recall from memory and show a preference for online updating. We demonstrated that even under these conditions, relying on memory is an effective strategy for performing evaluation, and discuss implications for understanding how people resolve the trade-off between online and retrospective evaluation.

Introduction Patients presenting with new onset interstitial lung disease (ILD) should be assessed for secondary, potentially treatable, causes. Some patients with rheumatic disease may present with ILD as the first manifestation of their condition. Early diagnosis and treatment of an underlying rheumatic disease can improve patient outcome. As autoimmune screening has evolved to include extended myositis and scleroderma panels, increasing numbers of patients with ILD are being referred for review by a rheumatologist. This case highlights one such patient diagnosed with new onset ILD during an acute hospital admission but subsequently found to have an underlying connective tissue disease (CTD). Case description A 54-year-old previously fit and well man presented to the Emergency Department with a three-month history of progressively worsening shortness of breath and dry cough. He denied any other symptoms, including those in keeping with a connective tissue disease (CTD). His past medical history was unremarkable. His father had a possible diagnosis of Sjögren’s syndrome and his sister had Sjögren’s syndrome with ILD. He had a 20 pack year smoking history. On admission his could only walk ten meters before having to stop due to shortness of breath. On auscultation of his chest he had fine inspiratory crepitations in the mid and lower zones. Blood tests revealed an elevated c-reactive protein (CRP) of 96 and erythrocyte sedimentation rate (ESR) of 120. He failed to improve with intravenous antibiotics and his CRP rose to 122. Computer tomography (HRCT) of the chest, abdomen and pelvis revealed bilateral reticulation peripherally in the mid and lower zones and paraseptal/centrilobular emphysematous changes in the upper zones. Pulmonary function tests (PFTs) demonstrated normal spirometry but reduced gas transfer. Anti-cyclic citrullinated peptide (anti-CCP) antibodies, rheumatoid factor, anti-neutrophil cytoplasmic antibodies (ANCA) and HIV screen were negative. Creatine kinase was normal. ANA was positive, with positive anti-Ro-52 antibodies and positive anti-PL12 on an extended myositis panel. A diagnosis of anti-synthetase syndrome was made. He was treated with three 1 gram doses of intravenous methylprednisolone on consecutive days then switched to 40mg of oral prednisolone daily. His inflammatory markers improved and he was discharged home. Monthly cyclophosphamide infusions were commenced and he has received two doses thus far. Although subjectively the patient does not report much improvement in his breathing as yet, he attends his appointments independently and is able to walk over 50 meters without stopping. Repeat PFTs and HRCT chest are scheduled. Discussion Patients presenting with ILD with no identifiable cause should be assessed and screened for CTDs. Evaluation should include a thorough history and examination, looking for associated conditions. ILD may be associated with rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, anti-synthetase syndrome, sarcoidosis, Sjogren’s syndrome, mixed connective tissue disease and systemic lupus erythematous (SLE). Pulmonary function tests may demonstrate a restrictive pattern on spirometry, although this can be normal. Gas transfer is often reduced and a carbon monoxide transfer factor of If no clear alternative cause of ILD (eg. drugs, occupational exposure, inhaled substances, infection, radiation) then physicians should consider sending bloods to help excludes CTDs, including creatine kinase, rheumatoid factor, anti-CCP antibodies, anti-nuclear antibodies (with extended myositis and scleroderma panels) and ANCA, even in asymptomatic patients. Case series have demonstrated that ILD may be the only presenting feature in a proportion of those with anti-synthetase syndrome, particularly in patients with anti-PL7 or PL-12. The classic triad of clinical features for anti-synthetase syndrome consists of ILD, myositis and arthritis (mechanic’s hands). Our patient had no CTD symptoms at presentation but has gone on to develop Raynaud’s and stiffness in his fingers over the last 6 months. He has not at any stage had evidence of myositis, either clinically or serologically, which is in keeping with case series of patients with ILD and PL-12 positivity reporting a proportion as being amyopathic. Particular factors that should prompt screening for anti-synthetase syndrome include female gender, middle age, clinical signs suggestive of a CTD and an NSIP pattern on HRCT. Key learning points Rheumatic conditions which can present with ILD include rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, anti-synthetase syndrome, sarcoidosis, Sjögren’s syndrome, mixed connective tissue disease and SLE.Newly presenting ILD patients with no identifiable cause should be checked for rheumatoid factor, anti-CCP antibodies, anti-nuclear antibodies (with extended myositis and scleroderma panel) and ANCA. ILD associated with anti-synthetase syndrome, polymyositis or dermatomyositis often warrants early treatment with steroid and cyclophosphamide or another immunosuppressive agent such as rituximab. Patient characteristics which should prompt screening for anti-synthetase syndrome with extended myositis panel testing include clinical suspicion of CTD, female gender, middle age, CTD symptoms or signs and NSIP pattern on HRCT. All patients presenting with ILD should have pulmonary function tests and imaging to assess severity of disease. Conflicts of interest The authors have declared no conflicts of interest.

Neuroethics is central to the Australian Brain Initiative’s aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative. Refereed/Peer-reviewed

In this paper, we draw connections between reward processing and cognition by behaviourally testing the implications of neurobiological theories of reward processing on memory. Single-cell neurophysiology in non-human primates and imaging work in humans suggests that the dopaminergic reward system responds to different components of reward: expected value; outcome or prediction error; and uncertainty of reward (Schultz et al., 2008). The literature on both incidental and motivated learning has focused on understanding how expected value and outcome—linked to increased activity in the reward system—lead to consolidation-related memory enhancements. In the current study, we additionally investigate the impact of reward uncertainty on human memory. The contribution of reward uncertainty—the spread of the reward probability distribution irrespective of the magnitude—has not been previously examined. To examine the effects of uncertainty on memory, a word-learning task was introduced, along with a surprise delayed recognition memory test. Using Bayesian model selection, we found evidence only for expected value as a predictor of memory performance. Our findings suggest that reward uncertainty does not enhance memory for individual items. This supports emerging evidence that an effect of uncertainty on memory is only observed in high compared to low risk environments.

This article was migrated. The article was marked as recommended. BackgroundResearch about clinical reasoning has tended to focus on the individual, assessing their ability to perform clinical reasoning tasks. However, recent studies have noted that clinical reasoning varies with the clinical context.ObjectivesThe purpose of this narrative review is to examine how the context can affect physicians clinical reasoning skills.MethodsA narrative literature review was conducted by searching PubMed, PsycINFO and Embase via Ovid using the search terms clinical OR critical AND thinking OR judgement OR reasoning. Of 22,296 results found, 25 studies were found to be relevant to our review.ResultsMost studies focused on diagnostic skills. Contexts affecting clinical reasoning fell into three broad categories: patient, physician and environmental (the physical and social setting) factors. Patient contexts researched included factors both personal to the patient and their physical disease manifestations. Physician contexts included experience, age, exposure to similar diagnoses, incorrect diagnostic suggestion, emotions, and the use of reflection and checklists. Environmental contexts included time pressure, unfamiliarity with surroundings, dealing with uncertainty and high-stakes outcomes. The effect of applying more than one contextual factor increasing cognitive load, was explored.ConclusionThis original review suggests that the context can affect a physician's clinical reasoning abilities. This review identifies areas for continued research, including which contexts have a negative or positive impact, and the effect of multiple contexts (cognitive loading) on clinical reasoning. Further empirical research is needed to investigate these areas in more depth and to establish how far these benefits have an impact in practice.

© 2019 Elsevier Inc. Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.

BACKGROUND:Obesity is related to a tendency to discount the future. Information regarding inter-meal interval (IMI) allows meal planning. We sought to assess how obese, overweight, and lean people select portion sizes based on the length of an IMI. We hypothesised that individuals with a high BMI would discount information about the IMI. In addition, we investigated how reduced sensitivity to IMIs relates to monetary temporal discounting.METHODS:Participants (lean, n=35; overweight, n=31; obese, n=22), selected lunchtime portion sizes in response to information about the timings of their next meal. In seven trials, the time of the IMI was systematically manipulated, ranging from ‘right now’ to ‘8 h’. Participants then completed a monetary temporal discounting task. BMI was included as a continuous measure. For each participant, we conducted a linear regression of portion size on IMI to yield a gradient that reflected reduced sensitivity to future meal timings.RESULTS:As expected, participants selected larger portion sizes in response to a long IMI. Consistent with our hypothesis, individuals with a high BMI discounted information about the IMI (β=−3.49, P=0.015; confidence interval (CI) 6.29 to −0.70). Monetary discounting also negatively predicted BMI (β=−8.1, P=0.003; CI=−13.43 to −2.77), but did not correlate with IMI sensitivity (P>0.05).CONCLUSIONS:These results are the first to demonstrate that temporal discounting operates in planning from one meal to the next, and is more prevalent in obese and overweight, relative to lean individuals. Participants with a high BMI discounted concerns about potential future fullness and hunger in the IMI. Our observations might begin to explain associations between obesity and irregular meal timings or help to form the basis for a targeted intervention that promotes future thinking in meal planning.

‘Dietary’ delay discounting is typically framed as a trade-off between immediate rewards and long-term health concerns. Our contention is that prospective thinking also occurs over shorter periods, and is engaged to select portion sizes based on the interval between meals (inter-meal interval; IMI). We sought to assess the extent to which the length of an IMI influences portion-size selection. We predicted that delay discounters would show ‘IMI insensitivity’ (relative lack of concern about hunger or fullness between meals). In particular, we were interested in participants' sensitivity to an uncertain IMI. We hypothesized that when meal times were uncertain, delay discounters would be less responsive and select smaller portion sizes. Participants (N = 90) selected portion sizes for lunch. In different trials, they were told to expect dinner at 5pm, 9pm, and either 5pm or 9pm (uncertain IMI). Individual differences in future-orientation were measured using a monetary delay-discounting task. Participants chose larger portions when the IMI was longer (p

Introduction Telomere length is shortened in patients with idiopathic aplastic anemia (AA) and other bone marrow failure disorders (BMFD) and predicts risk of clonal evolution (CE), relapse and overall survival (OS). Telomereopathies predominantly cause bone marrow failure, are multi-systemic disorders with variable penetrance, and may involve inter-play of other factors in disease manifestation and organ affliction. Telomere length (TL) in AA and other hypocellular BMFD, independent of mutations in telomere genes (TGC), has not been studied as a scoring tool, as well predicting the risk of affliction of other organ/systems in these disorders. We systematically review a large cohort of 472 patients in a single centre with AA/BMFD using TL and TGC analysis as a discriminator, to study risk of CE and OS, manifesting with liver/lung and skin complications, cancer predisposition and likelihood of a family member presenting with cytopenias. Methods We screened 1060 consecutive patients at a single centre from the years 2011-18, with AA or unexplained cytopenias for telomere length (TL) analysis using a multiplex qPCR methodology as described by Cawthon et al. 472 (44.5%) patients had TL less than the 25th centile, of whom 243 had Results Table attached. The median age and gender across the 3 cohorts studied (TL 10-25th centile, A third of patients with BMFD and TL TL does not correlate with the manifestation and presence of liver, respiratory and skin problems of telomere disease. TL in BMFD does not associate with increased predisposition to cancer, as their presence was not statistically significant across the 3 groups. Disease manifestation with bone marrow failure, haematological indices, need for blood transfusions, presence of a PNH clone and karyotypic abnormalities, including complex and monosomal karyotype were not dissimilar across the 3 TL cohorts. Not surprisingly, there were more family members with features of cytopenias and BMFD, on screening of patients with a confirmed TGC mutation. TL did not predict a difference in treatment strategies used across the 3 groups, although more patients with a TGC mutation received anabolic steroids. The risk of clonal evolution to PNH or MDS/AML and overall survival was again similar across the 3 TL cohorts with an OS of 93% at 1078 days follow-up for the entire cohort. Conclusion TL can reliably be used as a screening tool to investigate patients for further TGC mutation analysis in patients with AA or BMFD. Heterozygous state mutations in TERT are the commonest, and can be associated with mutations in other TGC genes, particularly RTEL1 and TERC. This may cause a compounding factor in shortening the TL further. However, TL TL and TGC mutation analysis in a single centre study from 2011-18. Table Disclosures Kizilors: Incyte biosciences: Research Funding. Mufti:Celgene: Consultancy, Research Funding.

Introduction Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualise the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies – in the form of combinations and altered durations of existing treatments, as well as newer drug therapies. Sources of data Pubmed and Embase were searched for randomised controlled trials of new therapies for osteoporosis. These searches were supplemented with material presented in abstract form at international meetings Areas of agreement New drugs that appear promising in the treatment of osteoporosis include the cathepsin K inhibitor, monoclonal antibodies against sclerostin, and parathyroid hormone related peptide. Areas of controversy Separate to the development of novel drug therapies is the issue of how best to use agents that are currently available to us; specifically which agent to choose, alone or in combination; duration of therapy; how best to identify patients at highest risk of fracture, and to ensure the highest possible adherence to medication. Many of these issues have been addressed in other excellent review papers, and will not be considered in detail here. Growing points As with all new treatments, we await results of long term use, and experience in ‘real life’ patient populations Areas timely for developing research As alluded to above, data are urgently required regarding the optimal duration of therapy; use of combination therapy; ordering of therapies for best therapeutic effect. As stratified medicine becomes more strongly considered in all areas of therapy, its merits in osteoporosis as in other musculoskeletal conditions, is timely and valuable.

Biologic dose reduction strategies, for patients with inflammatory rheumatic diseases, have been assessed in multiple studies to assess outcomes compared to ongoing maintenance dosing. Whilst cessation in established disease usually leads to disease flare, dose tapering approaches for those achieving low disease activity often appear to be successful in the short term. However, tapering can be associated with a higher risk of losing disease control and rates of recapture of disease control using the original biologic dose vary between studies. Over relatively short periods of follow-up, a number of studies have shown no statistical difference in radiographic progression in patients tapering or discontinuing biologics. However, a Cochrane review found that radiographic and functional outcomes may be worse after TNF inhibitor discontinuation, and over long-term disease follow-up flares have been associated with radiographic progression and worse patient reported outcomes. To date, no studies of biological therapy dose reduction have specifically investigated the risk of increased immunogenicity or the effects on cardiovascular risk and other co-morbidities, although these remain important potential risks. In addition, whether there are greater dangers in certain dose reduction approaches such as a reduction in dose at the same frequency or a spacing of doses is not established.

We hypothesised that embedding educational learning in a game would improve learning outcomes, with increased engagement and recruitment of cognitive resources evidenced by increased activation of working memory network (WMN) and deactivation of Default Mode Network (DMN) regions. In an fMRI study, we compared activity during periods of learning in three conditions that were increasingly game-like: Study-only (when periods of learning were followed by an exemplar question together with its correct answer), Self-quizzing (when periods of learning were followed by a multiple choice question in return for a fixed number of points) and Game-based (when, following each period of learning, participants competed with a peer to answer the question for escalating, uncertain rewards). DMN hubs deactivated as conditions became more game-like, alongside greater self-reported engagement and, in the Game-based condition, higher learning scores. These changes did not occur with any detectable increase in WMN activity. Additionally, ventral striatal activation was associated with responding to questions and receiving positive question\ud feedback. Results support the significance of DMN deactivation for educational learning, and are aligned with recent evidence suggesting DMN and WMN activity may not always be anti-correlated.

We grow hydrogenated amorphous silicon–germanium alloys by the hot-wire chemical vapor deposition (HWCVD) technique at deposition rates between 0.5 and 1.4 nm per second. We prepared a set of these alloys to determine the concentrations of the alloying elements as measured by various techniques. This set consists of samples throughout the range of germanium alloying from 0% (a-Si:H) to 100% (a-Ge:H). We find that by making the appropriate calibrations and corrections, our compositional measurements agree between the various techniques. Nuclear reaction analysis (NRA), Fourier transform infrared spectroscopy (FTIR)and secondary ion mass spectrometry (SIMS) all yield similar hydrogen contents, within ±20% for each sample. Electron probe micro-analysis (EPMA) and SIMS yield silicon and germanium contents within ±7% of each other with results being confirmed by Rutherford backscattering (RBS). EPMA oxygen measurements are affected by oxidized surface layers, thus these data show larger O concentrations than those measured by SIMS.

We report the longitudinal optical (LO) phonon frequencies for thin films of the ternary alloy CdSxTe1−x and their composition dependence for the full range of x values from pure CdTe to pure CdS. Pulsed laser deposition was used to prepare the polycrystalline thin films including compositions well inside the miscibility gap. We find that this ternary system exhibits a “two-mode” behavior with CdS- and CdTe-like longitudinal optic phonon modes. The modified random-element isodisplacement model yields a good description of the composition dependence of the LO phonon frequencies.

We successfully grow high-quality hydrogenated amorphous-silicon-germanium alloys (a-SiGe:H) by the hot-wire chemical-vapor deposition (HWCVD) technique using silane and germane gas mixtures. These alloys display electronic properties as good as those grown by the plasma-enhanced chemical-vapor deposition (PECVD) technique, when comparing materials with the same optical bandgaps. However, we grow materials with good electrical properties at high deposition rates—up to 40 Å/s, compared to 1–4 Å/s for PECVD materials. Our alloys exhibit similar trends with increasing Ge content to alloys grown by PECVD. The defect density, the dark conductivity, and the degree of nanostructural heterogeneity (as measured by small-angle X-ray scattering) all increase with increasing germanium content in the alloy. The nanostructural heterogeneity displays a sharp transition between 9 at.% and 14 at.% germanium. PECVD- grown a-SiGe:H alloys exhibit a similar transition at 20 at.% Ge. The photoconductivity and the ambipolar diffusion length of the alloys decrease with increasing germanium content. For a fixed silane-to-germane gas ratio, all material properties improve substantially when increasing substrate temperature (Tsub) from 220°C to 375°C. Increasing Tsub also narrows the optical bandgap and lowers the hydrogen content in the alloys for the same germane-to-silane gas ratio.

We have studied interdiffusion between CdS and CdTe in solar cells, bilayers, and in alloy films by Rutherford backscattering (RBS), Raman scattering, photoluminescence (PL), optical absorption and X-ray diffraction. The cells and films were fabricated by laser physical vapor deposition (LPVD) or by RF sputtering (RFS). We also have prepared films of the ternary alloy material (CdS/sub x/Te/sub 1-x/) by LPVD, related film composition to target composition by WDS, and obtained values for band bowing, lattice constant, phonon frequencies, and low temperature PL characteristics. The RBS spectra, obtained from thin bilayers of CdTe/CdS on fused silica, provide information on interdiffusion with /spl sim/200 /spl Aring/ depth resolution.